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Total Saponin from Korean Red Ginseng Inhibits Thromboxane A2 Production Associated Microsomal Enzyme Activity in Platelets

  • Lee, Dong-Ha (Department of Biomedical Laboratory Science, College of Biomedical Science and Engineering and Regional Research Center, Inje University) ;
  • Cho, Hyun-Jeong (Department of Biomedical Laboratory Science, College of Medical Science, Konyang University) ;
  • Kang, Hye-Yeon (Department of Biomedical Laboratory Science, College of Medical Science, Konyang University) ;
  • Rhee, Man-Hee (Laboratory of Veterinary Physiology & Signaling, College of Veterinary Medicine, Kyungpook National University) ;
  • Park, Hwa-Jin (Department of Biomedical Laboratory Science, College of Biomedical Science and Engineering and Regional Research Center, Inje University)
  • Received : 2011.09.07
  • Accepted : 2011.11.08
  • Published : 2012.01.11

Abstract

Ginseng, the root of Panax ginseng Meyer, has been used frequently in traditional oriental medicine and is popular globally. Ginsenosides, which are the saponins in ginseng, are the major components having pharmacological and biological activities, including anti-diabetic and anti-tumor activities. In this study, we investigated the effects of total saponin from Korean red ginseng(TSKRG) on thrombin-produced thromboxane $A_2$ ($TXA_2$), an aggregating thrombogenic molecule, and its associated microsomal enzymes cyclooxygenase (COX)-1 and $TXA_2$ synthase (TXAS). Thrombin (0.5 U/mL) increased $TXA_2$ production up to 169 ng/$10^8$ platelets as compared with control (0.2 ng/$10^8$ platelets). However, TSKRG inhibited potently $TXA_2$ production to the control level in a dose-dependent manner, which was associated with the strong inhibition of COX-1 and TXAS activities in platelet microsomes having cytochrome c reductase activity. The results demonstrate TSKRG is a beneficial traditional oriental medicine in platelet-mediated thrombotic diseases via suppression of COX-1 and TXAS to inhibit production of $TXA_2$.

Keywords

References

  1. Schwartz SM, Heimark RL, Majesky MW. Developmental mechanisms underlying pathology of arteries. Physiol Rev 1990;70:1177-1209.
  2. Berridge MJ, Irvine RF. Inositol trisphosphate, a novel second messenger in cellular signal transduction. Nature 1984;312:315-321. https://doi.org/10.1038/312315a0
  3. Jennings LK. Role of platelets in atherothrombosis. Am J Cardiol 2009;103(3 Suppl):4A-10A.
  4. Pasqui AL, Capecchi PL, Ceccatelli L, Mazza S, Gistri A, Laghi Pasini F, Di Perri T. Nitroprusside in vitro inhibits platelet aggregation and intracellular calcium translocation. Effect of haemoglobin. Thromb Res 1991;61:113-122.
  5. Nishikawa M, Tanaka T, Hidaka H. $Ca^{2+}$-calmodulindependent phosphorylation and platelet secretion. Nature 1980;287:863-865. https://doi.org/10.1038/287863a0
  6. Murakami K, Chan SY, Routtenberg A. Protein kinase C activation by cis-fatty acid in the absence of $Ca^{2+}$ and phospholipids. J Biol Chem 1986;261:15424-15429.
  7. Hamberg M, Svensson J, Samuelsson B. Thromboxanes: a new group of biologically active compounds derived from prostaglandin endoperoxides. Proc Natl Acad Sci U S A 1975;72:2994-2998. https://doi.org/10.1073/pnas.72.8.2994
  8. Cattaneo M, Tenconi PM, Lecchi A, Mannucci PM. In vitro effects of picotamide on human platelet aggregation, the release reaction and thromboxane $B_2$ production. Thromb Res 1991;62:717-724. https://doi.org/10.1016/0049-3848(91)90375-7
  9. Moriyama T, Takamura H, Narita H, Tanaka K, Matsuura T, Kito M. Elevation of cytosolic free $Ca^{2+}$ is directly evoked by thromboxane $A_2$ in human platelets during activation with collagen. J Biochem 1988;103:901-902.
  10. Patrono C. Aspirin as an antiplatelet drug. N Engl J Med 1994;330:1287-1294. https://doi.org/10.1056/NEJM199405053301808
  11. Cipollone F, Patrignani P, Greco A, Panara MR, Padovano R, Cuccurullo F, Patrono C, Rebuzzi AG, Liuzzo G, Quaranta G et al. Differential suppression of thromboxane biosynthesis by indobufen and aspirin in patients with unstable angina. Circulation 1997;96:1109-1116. https://doi.org/10.1161/01.CIR.96.4.1109
  12. Patrono C. Aspirin: new cardiovascular uses for an old drug. Am J Med 2001;110:62S-65S. https://doi.org/10.1016/S0002-9343(00)00645-8
  13. Ichikawa K, Tazawa S, Hamano S, Kojima M, Hiraku S. Effect of ozagrel on locomotor and motor coordination after transient cerebral ischemia in experimental animal models. Pharmacology 1999;59:257-265. https://doi.org/10.1159/000028328
  14. Park HJ, Lee JH, Song YB, Park KH. Effects of dietary supplementation of lipophilic fraction from Panax ginseng on cGMP and cAMP in rat platelets and on blood coagulation. Biol Pharm Bull 1996;19:1434-1439. https://doi.org/10.1248/bpb.19.1434
  15. Park HJ, Rhee MH, Park KM, Nam KY, Park KH. Effect of non-saponin fraction from Panax ginseng on cGMP and thromboxane $A_2$ in human platelet aggregation. J Ethnopharmacol 1995;49:157-162. https://doi.org/10.1016/0378-8741(95)01317-2
  16. Rhee MH, Park KM, Park HJ, Nam KY, Park KH. Inhibition of serotonin release by lipophilic fraction from Korean red ginseng. Korean J Ginseng Sci 1993;17:127-130.
  17. Park HJ, No YH, Rhee MH, Park KM, Park KH. Effects of protein fractions and ginsenosides from Panax ginseng C.A. Meyer on substrate phosphorylation by a catalytic fragment of protein kinase. Korean Biochem J 1994;27:280-283.
  18. Kuo SC, Teng CM, Lee JC, Ko FN, Chen SC, Wu TS. Antiplatelet components in Panax ginseng. Planta Med 1990;56:164-167. https://doi.org/10.1055/s-2006-960916
  19. Lee WM, Kamruzzaman SM, Song YB, Cho JY, Park HJ, Rhee MH. Inhibitory activities of red ginseng acidic polysaccharide in platelet aggregation. J Ginseng Res 2008;32:73-78. https://doi.org/10.5142/JGR.2008.32.1.073
  20. Park JM, Rhee MH, Shin HJ, Song YB, Hyun HC, Park KH, Cho HJ, Choi SA, Kang HC, Kim KJ et al. Inhibitory effects of Panaxatriol from Panax ginseng C.A. Meyer on phosphoinositide breakdown induced by thrombin in platelets. J Ginseng Res 2008;32:107-113. https://doi.org/10.5142/JGR.2008.32.2.107
  21. Park KM, Rhee MH, Park HJ. Panaxadiol and panaxatriol from Panax ginseng C.A. Meyer inhibit the synthesis of thromboxane $A_2$ in adrenaline-stimulated human platelet aggregation. Korean J Ginseng Sci 1994;18:44-48.
  22. Park HJ, Rhee MH, Park KM, Nam KY, Park KH. Panaxadiol from Panax ginseng C.A. Meyer inhibits synthesis of thromboxane $A_2$ in platelet aggregation induced by thrombin. Korean J Ginseng Sci 1993;17:131-134.
  23. Kimura Y, Okuda H, Arichi S. Effects of various ginseng saponins on 5-hydroxytryptamine release and aggregation in human platelets. J Pharm Pharmacol 1988;40:838-843. https://doi.org/10.1111/j.2042-7158.1988.tb06285.x
  24. Lee WM, Kim SD, Park MH, Cho JY, Park HJ, Seo GS, Rhee MH. Inhibitory mechanisms of dihydroginsenoside $Rg_3$ in platelet aggregation: critical roles of ERK2 and cAMP. J Pharm Pharmacol 2008;60:1531-1536. https://doi.org/10.1211/jpp.60.11.0015
  25. Reuter H, Niemeyer G, Gross R. Studies of the aggregation of human blood platelets. 3. On the inhibition of platelet aggregation in EDTA plasma following incubation at 37 degrees C. Klin Wochenschr 1967;45:1147-1149. https://doi.org/10.1007/BF01727398
  26. Lagarde M, Menashi S, Crawford N. Localisation of phospholipase $A_2$ and diglyceride lipase activities in human platelet intracellular membranes. FEBS Lett 1981;124:23-26. https://doi.org/10.1016/0014-5793(81)80045-2
  27. Ruggeri ZM. Platelets in atherothrombosis. Nat Med 2002;8:1227-1234. https://doi.org/10.1038/nm1102-1227
  28. FitzGerald GA. Mechanisms of platelet activation: thromboxane $A_2$ as an amplifying signal for other agonists. Am J Cardiol 1991;68:11B-15B. https://doi.org/10.1016/0002-9149(91)90379-Y
  29. Clutton P, Folts JD, Freedman JE. Pharmacological control of platelet function. Pharmacol Res 2001;44:255-264. https://doi.org/10.1006/phrs.2001.0861
  30. Halushka PV, Allan CJ, Davis-Bruno KL. Thromboxane $A_2$ receptors. J Lipid Mediat Cell Signal 1995;12:361-378. https://doi.org/10.1016/0929-7855(95)00023-J
  31. Teng CM, Kuo SC, Ko FN, Lee JC, Lee LG, Chen SC, Huang TF. Antiplatelet actions of panaxynol and ginsenosides isolated from ginseng. Biochim Biophys Acta 1989;990:315-320. https://doi.org/10.1016/S0304-4165(89)80051-0
  32. Samuelsson B. Biosynthesis and metabolism of prostaglandins. Prog Biochem Pharmacol 1967;3:59-70.
  33. Sun FF, Chapman JP, McGuire JC. Metabolism of prostaglandin endoperoxide in animal tissues. Prostaglandins 1977;14:1055-1074. https://doi.org/10.1016/0090-6980(77)90285-4
  34. Savage B, Cattaneo M, Ruggeri ZM. Mechanisms of platelet aggregation. Curr Opin Hematol 2001;8:270-276. https://doi.org/10.1097/00062752-200109000-00002
  35. Lee SR, Park JH, Choi KJ, Kim ND. Inhibitory effects of ginsenoside $Rg_3$ on platelet aggregation and its mechanism of action. Korean J Ginseng Sci 1997;21:132-140.
  36. Pace-Asciak CR, Reynaud D, Demin P, Aslam R, Sun A. A new family of thromboxane receptor antagonists with secondary thromboxane synthase inhibition. J Pharmacol Exp Ther 2002;301:618-624. https://doi.org/10.1124/jpet.301.2.618
  37. Moers A, Wettschureck N, Offermanns S. G13-mediated signaling as a potential target for antiplatelet drugs. Drug News Perspect 2004;17:493-498. https://doi.org/10.1358/dnp.2004.17.8.863692
  38. Cho HJ, Choi SA, Kim CG, Hong JH, Park HJ, Park HJ. Dietary spinach saponin-enriched lipophilic fraction inhibits platelet aggregation and blood coagulation. J Med Food 2011;14:784-791. https://doi.org/10.1089/jmf.2010.1411

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